Use of adipose-derived mesenchymal stem cells in keratoconjunctivitis sicca in a canine model
Antonio J Villatoro, Viviana Fernández, Silvia Claros, Gustavo A Rico-Llanos, José Becerra, José A Andrades, Antonio J Villatoro, Viviana Fernández, Silvia Claros, Gustavo A Rico-Llanos, José Becerra, José A Andrades
Abstract
Keratoconjunctivitis sicca (KCS) or dry eye disease (DED) is an immune-mediated multifactorial disease, with high level of prevalence in humans and dogs. Our aim in this study was to investigate the therapeutic effects of allogeneic adipose-derived mesenchymal stromal cells (Ad-MSCs) implanted around the lacrimal glands in 12 dogs (24 eyes) with KCS, which is refractory to current available treatments. Schirmer tear test (STT) and ocular surface integrity were assessed at 0 (before treatment), 3, 6, and 9 months after treatment. Average STT values and all clinical signs showed a statistically significant change (P < 0.001) during the follow-up with reduction in all ocular parameters scored: ocular discharge, conjunctival hyperaemia, and corneal changes, and there were no signs of regression or worsening. Implanted cells were well tolerated and were effective reducing clinical signs of KCS with a sustained effect during the study period. None of the animals showed systemic or local complications during the study. To our knowledge, this is the first time in literature that implantation of allogeneic Ad-MSCs around lacrimal glands has been found as an effective therapeutic alternative to treat dogs with KCS. These results could reinforce a good effective solution to be extrapolated to future studies in human.
Figures
References
- Gupta N., Prasad I., Himashree G., D'Souza P. Prevalence of dry eye at high altitude: a case controlled comparative study. High Altitude Medicine and Biology. 2008;9(4):327–334. doi: 10.1089/ham.2007.1055.
- Smith J. A., Albenz J., Begley C., et al. The epidemiology of dry eye disease: report of the epidemiology subcommittee of the international Dry Eye WorkShop (2007) Ocular Surface. 2007;5(2):93–107. doi: 10.1016/S1542-0124(12)70082-4.
- Abelson M. B., Ousler G. W., III, Maffei C. Dry eye in 2008. Current Opinion in Ophthalmology. 2009;20(4):282–286. doi: 10.1097/ICU.0b013e32832b7578.
- Barabino S., Dana M. R. Animal models of dry eye: a critical assessment of opportunities and limitations. Investigative Ophthalmology and Visual Science. 2004;45(6):1641–1646. doi: 10.1167/iovs.03-1055.
- Stevenson W., Chauhan S. K., Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Archives of Ophthalmology. 2012;130(1):90–100. doi: 10.1001/archophthalmol.2011.364.
- Williams D. L. Immunopathogenesis of Keratoconjunctivitis sicca in the dog. Veterinary Clinics of North America: Small Animal Practice. 2008;38(2):251–268. doi: 10.1016/j.cvsm.2007.12.002.
- Worster A. A., Nixon A. J., Brower-Toland B. D., Williams J. Effect of transforming growth factor β1 on chondrogenic differentiation of cultured equine mesenchymal stem cells. American Journal of Veterinary Research. 2000;61(9):1003–1010. doi: 10.2460/ajvr.2000.61.1003.
- Lemp M. A. Management of dry eye disease. The American Journal of Managed Care. 2008;14(3):S88–S101.
- Murphy M. B., Moncivais K., Caplan A. I. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Experimental and Molecular Medicine. 2013;45(11, article e54) doi: 10.1038/emm.2013.94.
- Kapur S. K., Katz A. J. Review of the adipose derived stem cell secretome. Biochimie. 2013;95(12):2222–2228. doi: 10.1016/j.biochi.2013.06.001.
- Kang J. W., Kang K.-S., Koo H. C., Park J. R., Choi E. W., Park Y. H. Soluble factors-mediated immunomodulatory effects of canine adipose tissue-derived mesenchymal stem cells. Stem Cells and Development. 2008;17(4):681–693. doi: 10.1089/scd.2007.0153.
- Carrade D. D., Affolter V. K., Outerbridge C. A., et al. Intradermal injections of equine allogeneic umbilical cord-derived mesenchymal stem cells are well tolerated and do not elicit immediate or delayed hypersensitivity reactions. Cytotherapy. 2011;13(10):1180–1192. doi: 10.3109/14653249.2011.602338.
- Alonso M., Claros S., Becerra J., Andrades J. A. The effect of type I collagen on osteochondrogenic differentiation in adipose-derived stromal cells in vivo. Cytotherapy. 2008;10(6):597–610. doi: 10.1080/14653240802242084.
- Yagi H., Soto-Gutierrez A., Parekkadan B., et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplantation. 2010;19(6-7):667–679. doi: 10.3727/096368910X508762.
- Leto Barone A. A., Khalifian S., Lee W. P. A., Brandacher G. Immunomodulatory effects of adipose-derived stem cells: fact or fiction? BioMed Research International. 2013;2013:8. doi: 10.1155/2013/383685.383685
- de Bakker E., van Ryssen B., de Schauwer C., Meyer E. Canine mesenchymal stem cells: state of the art, perspectives as therapy for dogs and as a model for man. Veterinary Quarterly. 2013;33(4):225–233. doi: 10.1080/01652176.2013.873963.
- Quimby F. W., Schwartz R. S., Poskitt T., Lewis R. M. A disorder of dogs resembling Sjögren’s syndrome. Clinical Immunology and Immunopathology. 1979;12(4):471–476. doi: 10.1016/0090-1229(79)90052-7.
- Hamor R. E., Roberts S. M., Severin G. A., Chavkin M. J. Evaluation of results for Schirmer tear tests conducted with and without application of a topical anesthetic in clinically normal dogs of 5 breeds. American Journal of Veterinary Research. 2000;61(11):1422–1425. doi: 10.2460/ajvr.2000.61.1422.
- Dursun D., Wang M., Monroy D., et al. A mouse model of keratoconjunctivitis sicca. Investigative Ophthalmology & Visual Science. 2002;43(3):632–638.
- Zoukhri D. Mechanisms involved in injury and repair of the murine lacrimal gland: role of programmed cell death and mesenchymal stem cells. Ocular Surface. 2010;8(2):60–69. doi: 10.1016/S1542-0124(12)70070-8.
- Massingale M. L., Li X., Vallabhajosyula M., Chen D., Wei Y., Asbell P. A. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea. 2009;28(9):1023–1027. doi: 10.1097/ICO.0b013e3181a16578.
- Zhou X. Q., Wei R. L. Topical cyclosporine a in the treatment of dry eye: a systematic review and meta-analysis. Cornea. 2014;33(7):760–767. doi: 10.1097/ICO.0000000000000123.
- Barachetti L., Rampazzo A., Mortellaro C. M., Scevola S., Gilger B. C. Use of episcleral cyclosporine implants in dogs with keratoconjunctivitis sicca: pilot study. Veterinary Ophthalmology. 2014 doi: 10.1111/vop.12173.
- Schuh E. M., Friedman M. S., Carrade D. D., et al. Identification of variables that optimize isolation and culture of multipotent mesenchymal stem cells from equine umbilical-cord blood. American Journal of Veterinary Research. 2009;70(12):1526–1535. doi: 10.2460/ajvr.70.12.1526.
- Vieira N. M., Brandalise V., Zucconi E., Secco M., Strauss B. E., Zatz M. Isolation, characterization, and differentiation potential of canine adipose-derived stem cells. Cell Transplantation. 2010;19(3):279–289. doi: 10.3727/096368909X481764.
- Chung D. J., Hayashi K., Toupadakis C. A., Wong A., Yellowley C. E. Osteogenic proliferation and differentiation of canine bone marrow and adipose tissue derived mesenchymal stromal cells and the influence of hypoxia. Research in Veterinary Science. 2012;92(1):66–75. doi: 10.1016/j.rvsc.2010.10.012.
- Martinello T., Bronzini I., Maccatrozzo L., et al. Canine adipose-derived-mesenchymal stem cells do not lose stem features after a long-term cryopreservation. Research in Veterinary Science. 2011;91(1):18–24. doi: 10.1016/j.rvsc.2010.07.024.
- Bharti K., Rao M., Hull S. C., et al. Developing cellular therapies for retinal degenerative diseases. Investigative Ophthalmology & Visual Science. 2014;55(2):1191–1201. doi: 10.1167/iovs.13-13481.
- Holan V., Javorkova E. Mesenchymal stem cells, nanofiber scaffolds and ocular surface reconstruction. Stem Cell Reviews and Reports. 2013;9(5):609–619. doi: 10.1007/s12015-013-9449-0.
- Yamada A., Yokoo T., Yokote S., et al. Comparison of multipotency and molecular profile of MSCs between CKD and healthy rats. Human Cell. 2014;27(2):59–67. doi: 10.1007/s13577-013-0082-7.
- Efimenko A., Dzhoyashvili N., Kalinina N., et al. Adipose-derived mesenchymal stromal cells from aged patients with coronary artery disease keep mesenchymal stromal cell properties but exhibit characteristics of aging and have impaired angiogenic potential. Stem Cells Translational Medicine. 2014;3(1):32–41. doi: 10.5966/sctm.2013-0014.
- Wu W., Niklason L., Steinbacher D. M. The effect of age on human adipose-derived stem cells. Plastic and Reconstructive Surgery. 2013;131(1):27–37. doi: 10.1097/PRS.0b013e3182729cfc.
- Guercio A., Bella S. D., Casella S., Marco P. D., Russo C., Piccione G. Canine mesenchymal stem cells (MSCs): characterization in relation to donor age and adipose tissue-harvesting site. Cell Biology International. 2013;37(8):789–798. doi: 10.1002/cbin.10090.
- Wood J. A., Chung D. J., Park S. A., et al. Periocular and intra-articular injection of canine adipose-derived mesenchymal stem cells: An in vivo imaging and migration study. Journal of Ocular Pharmacology and Therapeutics. 2012;28(3):307–317. doi: 10.1089/jop.2011.0166.
- Takemitsu H., Zhao D., Ishikawa S., Michishita M., Arai T., Yamamoto I. Mechanism of insulin production in canine bone marrow derived mesenchymal stem cells. General and Comparative Endocrinology. 2013;189:1–6. doi: 10.1016/j.ygcen.2013.04.009.
- Dominici M., Le Blanc K., Mueller I., et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317. doi: 10.1080/14653240600855905.
- Hodgkiss-Geere H. M., Argyle D. J., Corcoran B. M., et al. Characterisation and differentiation potential of bone marrow derived canine mesenchymal stem cells. Veterinary Journal. 2012;194(3):361–368. doi: 10.1016/j.tvjl.2012.05.011.
- Dennis J. E., Carbillet J.-P., Caplan A. I., Charbord P. The STRO-1+ marrow cell population is multipotential. Cells Tissues Organs. 2002;170(2-3):73–82. doi: 10.1159/000046182.
- Redaelli S., Bentivegna A., Foudah D., et al. From cytogenomic to epigenomic profiles: monitoring the biologic behavior of in vitro cultured human bone marrow mesenchymal stem cells. Stem Cell Research and Therapy. 2012;3(6, article 47) doi: 10.1186/scrt138.
- Binato R., de Souza Fernandez T., Lazzarotto-Silva C., et al. Stability of human mesenchymal stem cells during in vitro culture: considerations for cell therapy. Cell Proliferation. 2013;46(1):10–22. doi: 10.1111/cpr.12002.
- Xu J., Wang D., Liu D., et al. Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjogren syndrome. Blood. 2012;120(15):3142–3151. doi: 10.1182/blood-2011-11-391144.
- Foulks G. N., Pflugfelder S. C. New testing options for diagnosing and grading dry eye disease. American Journal of Ophthalmology. 2014;157(6):1122–1129. doi: 10.1016/j.ajo.2014.03.002.
Source: PubMed